The multi-receptor inhibitor axitinib reverses tumor-induced immunosuppression and potentiates treatment with immune-modulatory antibodies in preclinical murine models
- 658 Downloads
Cancer immunotherapies have significantly improved the prognosis of cancer patients. Despite the clinical success of targeting inhibitory checkpoint receptors, including PD-1 and/or CTLA-4 on T cells, only a minority of patients derive benefit from these therapies. New strategies to improve cancer immunotherapy are therefore needed. Combination therapy of checkpoint inhibitors with targeted agents has promisingly shown to increase the efficacy of immunotherapy. Here, we analyzed the immunomodulatory effects of the multi-receptor tyrosine kinase inhibitor axitinib and its efficacy in combination with immunotherapies. In different syngeneic murine tumor models, axitinib showed therapeutic efficacy that was not only mediated by VEGF–VEGFR inhibition, but also through the induction of anti-cancer immunity. Mechanistically, a significant reduction of immune-suppressive cells, including a decrease of tumor-promoting mast cells and tumor-associated macrophages was observed upon axitinib treatment. Inhibition of mast cells by axitinib as well as their experimental depletion led to reduced tumor growth. Of note, treatment with axitinib led to an improved T cell response, while the latter was pivotal for the therapeutic efficacy. Combination with immune checkpoint inhibitors anti-PD-1 and anti-TIM-3 and/or agonistic engagement of the activating receptor CD137 resulted in a synergistic therapeutic efficacy. This demonstrates non-redundant immune activation induced by axitinib via modulation of myeloid and mast cells. These findings provide important mechanistic insights into axitinib-mediated anti-cancer immunity and provide rationale for clinical combinations of axitinib with different immunotherapeutic modalities.
KeywordsCancer immunology Hematopoietic stem cell Mast cell Tumor-associated macrophage Tyrosine kinase inhibitor
Bone marrow-derived mast cell
CC-chemokine ligand 2
Fms-like tyrosine kinase 3
Metastatic renal cell carcinoma
Platelet-derived growth factor
Stem cell factor
Tyrosine kinase inhibitor
Vascular endothelial growth factor receptor
We thank Masato Kubo for providing the Mas-TRECK mice for our experiment. We also thank Petra Herzig and Béatrice Dolder Schlienger for their technical support.
PM planned and performed experiments. MB performed experiments. HL and PM evaluated the data and designed the figures. LD’ and ASK analyzed the results. HL, PM, ASK, AZ wrote the manuscript.
This work was supported by funding from a Grant from the Swiss Cancer League (KFS-3394-02-2014 to Alfred Zippelius), the Cancer League Basel (Krebsliga beider Basel, to Philipp Müller and Heinz Läubli), the Huggenberger Stiftung (to Heinz Läubli) as well as the Goldschmidt-Jacobson Foundation (to Heinz Läubli).
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
Mice were bought from Charles Rivers or bred in the animal facility of the Department of Biomedicine, University of Basel, Switzerland. Mas-TRECK mice were kindly provided by Masato Kubo. All animals were housed under specific pathogen-free conditions and in accordance with Swiss federal regulations (approved by the local ethical committee of Basel Stadt).
- 7.Hu-Lowe DD, Zou HY, Grazzini ML et al (2008) Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res 14:7272–7283. https://doi.org/10.1158/1078-0432.CCR-08-0652 CrossRefPubMedGoogle Scholar
- 9.Chowdhury S, McDermott DF, Voss MH, Hawkins RE, Aimone P, Voi M, Isabelle N, Wu Y, Infante JR (2017) A phase I/II study to assess the safety and efficacy of pazopanib (PAZ) and pembrolizumab (PEM) in patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol 35:suppl; abstr 4506CrossRefGoogle Scholar
- 10.Choueiri TK, Larkin JMG, Oya M et al (2017) First-line avelumab + axitinib therapy in patients (pts) with advanced renal cell carcinoma (aRCC): results from a phase Ib trial. J Clin Oncol 35:suppl; abstr 4504Google Scholar
- 11.Du Four S, Maenhout SK, De Pierre K, Renmans D, Niclou SP, Thielemans K, Neyns B, Aerts JL (2015) Axitinib increases the infiltration of immune cells and reduces the suppressive capacity of monocytic MDSCs in an intracranial mouse melanoma model. Oncoimmunology 4:e998107. https://doi.org/10.1080/2162402X.2014.998107 CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Stankevicius V, Vasauskas G, Bulotiene D, Butkyte S, Jarmalaite S, Rotomskis R, Suziedelis K (2016) Gene and miRNA expression signature of Lewis lung carcinoma LLC1 cells in extracellular matrix enriched microenvironment. BMC Cancer 16:789. https://doi.org/10.1186/s12885-016-2825-9 CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Yang Z, Zhang B, Li D, Lv M, Huang C, Shen GX, Huang B (2010) Mast cells mobilize myeloid-derived suppressor cells and Treg cells in tumor microenvironment via IL-17 pathway in murine hepatocarcinoma model. PLoS One 5:e8922. https://doi.org/10.1371/journal.pone.0008922 CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Du Four S, Maenhout SK, Benteyn D, De Keersmaecker B, Duerinck J, Thielemans K, Neyns B, Aerts JL (2016) Disease progression in recurrent glioblastoma patients treated with the VEGFR inhibitor axitinib is associated with increased regulatory T cell numbers and T cell exhaustion. Cancer Immunol Immunother 65:727–740. https://doi.org/10.1007/s00262-016-1836-3 CrossRefGoogle Scholar